Bioerodible contraceptive implant and methods of use thereof

ABSTRACT

A contraceptive drug delivery system is provided in the form of a controlled release, bioerodible pellet for subdermal implantation. The pellet is bioerodible, and provides for the sustained release of a contraceptive agent over an extended time period. Bioerosion products are water soluble, bioresorbed, or both, obviating the need for surgical removal of the implant. Methods of using the drug delivery system, including in female contraception, are also provided.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority under 35 U.S.C. § 119(e)(1) toprovisional U.S. Patent Application Ser. No. 62/401,167, filed Sep. 29,2016, the disclosure of which is incorporated by reference herein.

BACKGROUND OF THE INVENTION (1) Technical Field

The invention relates generally to controlled release drug deliverysystems, and more particularly relates to controlled releasecontraceptives. The invention finds utility in the fields of drugdelivery, pharmaceuticals, medicine, and public health.

(2) Description of Related Art

Many types of contraceptive formulations and drug delivery systems havebeen developed and commercialized over the years. The oral formulationEnovid 10, colloquially referred to as “the pill,” was approved for usein the United States in 1960, and was the first combined oralcontraceptive (COC). Enovid 10 contained a combination of an estrogenicsteroid, mestranol, at 9.85 mg, and a progestogen, norethynodrel, at 150μg. At the time, it was known that birth control could be achieved withprogestogen monotherapy, but the estrogenic component was added toenhance contraceptive efficacy and regulate vaginal bleeding. Enovid 10was administered on a daily basis, 21 days out from a woman's menstrualcycle.

The original oral contraceptive formulation was later modified to reduceserious side effects, particularly an increased incidence of venousthromboembolism (VTE), which has been attributed for the most part tothe estrogenic agent (the thrombotic risk was found to increase withincreasing doses of the estrogen). Accordingly, later oralcontraceptives contained a significantly lower dose of the estrogeniccomponent, generally ethinyl estradiol (EE), on the order of 20 μg to 50μg or even lower. In some subsequent contraceptive formulations, themore potent estrogenic agent 17β-estradiol (E₂) was substituted for EE,with chemical modifications of the compound, including micronization andesterification, made to improve its oral bioavailability. See Fruzzettiet al. (2012) Gynecol. Endocrinol. 28(5): 400-408 and Kuhnz et al.,“Pharmacokinetics of Exogenous Natural and Synthetic Estrogens andAntiestrogens” in Oettel et al., Eds., Handbook of ExperimentalPharmacology, Estrogens and Antioestrogens II (Berlin: Springer-Verlag,1999).

In addition to oral contraceptives, a host of alternative contraceptiveformulations and devices have been developed, including injectablecontraceptives and intrauterine devices (IUDs). While there are manyeffective methods of contraception available today, there is an ongoingneed for a method and/or formulation that fills a distinct gap in thecurrent contraceptive mix, i.e., a contraceptive that is intermediate induration of efficacy between existing injectable contraceptives andlonger-acting methods, such as implants and IUDs, providing reliablecontraceptive protection for on the order of one to two years. An idealformulation would also be: “forgettable” insofar as its effectivenesswould not depend on user compliance each day or at each coital act;removable before complete absorption, for women who decide to terminateuse of birth control; and biodegradable, so that removal is notrequired.

Contraceptive implants were first studied in efforts to develop such aformulation. One of the first studies of biodegradable implants for thedelivery of contraceptive drugs began in the 1970s with experimentsusing a biodegradable polyorthoester drug delivery matrix developed bythe ALZA Corporation and marketed under the trade name Alzamer™(initially Chronomer™). The polyorthoester matrix was advantageousinsofar as it was possible to control degradation via both hydrolysisand surface erosion, but preclinical testing studies with norethindroneand levonorgestrel were discontinued due to local irritation experiencedby study participants. See Heller et al. (1990) Biomaterials 11:659-665;and Pharriss et al. (1976) J. Reprod. Med. 17:91-97.

Early work using cholesterol as an excipient in contraceptive implantsbegan with initial trials in non-human primates in the late 1970s.Norethindrone was fused with cholesterol in a flash melting process.Several human clinical trials were conducted with fusedcholesterol-hormone pellets in the 70s, 80s and 90s; see, e.g., Beck etal. (1978) Contraception 18:497-505; Gupta et al. (1984) Contraception30:239-252; Joshi et al. (1985) Contraception 31:71-82; and Odlind etal. (1979) Contraception 19:639-648. A cholesterol-based norethindroneimplant (Annuelle™) developed by Endocon, Inc. underwent a Phase IIpharmacokinetics/pharmacodynamics and safety trial, but the releaseprofile was longer than the planned 12-month duration, and there wereadditional complications as well; see Raymond et al. (1996) Fertilityand Sterility 66:954-961.

Most of the work on contraceptive implants to date has involved the useof aliphatic polyesters, including polylactic acid (PLA), polyglycolicacid (PGA), polycaprolactone (PCL) and the copolymer of PLA and PGA,poly (lactic-co-glycolic acid) (PLGA); see Pitt et al. (1981) NIDA Res.Monogr. 28:232-53. Such materials have been viewed as attractivecandidates because their degradation products are naturally occurringmetabolites, i.e., lactic and glycolic acid. Additionally, thesepolymers have been used in products with prior regulatory approval,including sutures, meshes, screws, pins and plates for various surgicalapplications and for drug delivery. This precedent would likely shortenthe regulatory pathway for the approval of future products containingthese polymers. Another benefit of these materials is that copolymerssuch as PLGA can be engineered to have different monomer ratios allowingcontrol of degradation rates. A polycaprolactone-based contraceptiveimplant, Capronor™, was developed in the 1980s, designed to releaselevonorgestrel for a period in the range of 12 to 18 months and thendegrade. While not evidencing any problems with structural integrity,the product was abandoned because of skin irritation experienced bystudy participants, stability problems during storage, and a longrelease tail, explained infra.

More recently, contraceptive implants have been developed for thesustained release of etonogestrel (Implanon®, as well as the newerradio-opaque version, Nexplanon®, from Merck & Co.), which are intendedto provide contraceptive protection for up to three years. See Maddox etal. (2008) P&T 33(6):337-347, the prescribing information for Implanonand Nexplanon, and U.S. Pat. Nos. 4,957,119, 8,722,037 and 8,888,745.Like many other implants, however, Implanon and Nexplanon must besurgically removed as they are composed of non-bioerodible materials.

Accordingly, while these contraceptive dosage forms were found toprovide reasonably effective contraceptive protection, there werenumerous problems. Aside from the other issues noted in the abovediscussion, the need for removal of the implant represents more thanjust an inconvenience. In many areas of the world, women do not haveready access to reliable, quality surgical removal services, or tofacilities that could treat ensuing medical complication. Issues canarise with the formation of fibrous tissue around the implant, thefailure to locate implants that may have been inserted too deeply, pain,tissue damage, local infection, and nerve damage. Rumor or knowledge ofdifficulties associated with implant removal can deter women fromchoosing implants as a contraceptive method despite other inherentadvantages.

In addition, some implants have given rise to a long interval of timesubsequent to the last measured pharmacologically effective serum levelof the active agent (i.e., a serum level effective to provide reliablecontraceptive protection), during which time interval the active agentwas still detectable—and thus continuing to be released by the dosageform—but not present at a serum level sufficient to provide for reliablecontraception. See Raymond et al. (1996), supra, at 960. In theaforementioned study, involving a biodegradable implant, the dosage ofthe contraceptive agent fell below the minimum effective level for sometime, in some cases for as long as 18 months. This is an unacceptablylong time period during which contraceptive agent is still beingdelivered but at a dosage that is too low to provide a contraceptiveeffect. Other contraceptive implants that are bioerodible have alsoresulted in a “tail” or “tail period” as well, meaning that there is asignificant interval of time prior to complete bioerosion of the implantin which the contraceptive agent is being released, but at a dose belowthat needed to provide effective contraceptive protection. Aside fromthe failure of the implant to provide contraceptive efficacy during thistime, there is a concern that pregnancies conceived during the tailperiod (i.e., in the presence of low, sub-effective active agent levels)may have a danger of being ectopic. See Callahan (et al. (2015)Contraception 92:514-522.

There is, accordingly, an ongoing need in the art for a contraceptiveproduct that addresses the above drawbacks. An ideal extended releasecontraceptive implant would be (1) bioerodible, thereby obviating theneed for surgical removal, (2) composed of non-toxic, naturallyoccurring materials, (3) simple, inexpensive, and straightforward tomanufacture, without need for many steps, complicated equipment, toxicreagents, or a great deal of time, and (4) physically and chemicallystable during storage, handling, sterilization, handling, and a possibleearly removal procedure. An ideal contraceptive implant product wouldalso provide contraceptive protection over an extended time period,e.g., over a year or more, and also have a reduced tail period relativeto those observed with earlier contraceptive implants.

BRIEF SUMMARY OF THE INVENTION

Accordingly, the invention is directed to the aforementioned need in theart and, in one embodiment, provides a contraceptive drug deliverysystem in the form of a subdermally implantable pellet that provides forcontrolled, sustained release of a contraceptive agent throughout anextended drug delivery time period. The pellet comprises an amount of acontraceptive agent which, following subdermal implantation of at leastone of the pellets into a female individual, results in a serum level ofthe contraceptive agent sufficient to provide contraceptive efficacyduring the extended drug delivery time period. The contraceptive agentmay be a progestogen, or it may be a combination of active agents suchas a combination of a progestogen and an estrogen. The pellet isbioerodible in situ, so that there is no need for surgical removal ofthe pellet at the end of the drug delivery period. That is, anybioerosion products are water soluble, bioresorbable, or both, so as todissolve in or be absorbed by the body.

In one aspect of this embodiment, the contraceptive drug delivery systemis comprised of more than one pellet.

In another aspect of this embodiment, the contraceptive drug deliverysystem comprises two to six pellets, e.g., four or five pellets.

In another aspect of this embodiment, the pellet as a whole islipophilic, meaning that the total of any hydrophilic componentsrepresents less than 50 wt. % of the pellet.

In a related aspect, the total of any hydrophilic components representsless than 45 wt %, less than 40 wt. %, less than 35 wt. %, less than 30wt. %, less than 25 wt. %, less than 20 wt. %, less than 15 wt. %, lessthan 10 wt. %, or less than 5 wt. % of the pellet. It will thus beappreciated that the pellet may be substantially free of hydrophiliccomponents.

In another aspect of this embodiment, the pellet comprises a solid atthe temperature in the range of about 35° C. to about 40° C. Thisensures that the pellet will be in substantially solid form in the bodyand under storage conditions. In a preferred embodiment, a hot meltpellet manufacturing method is employed, as described infra, in whichcase the pellet composition should be flowable at a selected temperaturein the range of about 50° C. to about 250° C.

In an additional aspect of this embodiment, the pellet contains anexcipient composition that includes at least one excipient. Each pelletexcipient should be (a) a water-soluble and/or bioresorbable compound,or (b) transformed in situ to water-soluble and/or bioresorbablespecies, i.e., during pellet bioerosion, or both (a) and (b). In arelated aspect of this embodiment, pellet excipients are selected fromnaturally occurring materials, where the naturally occurring materialsmay be obtained from a biological source or chemically synthesized inwhole or in part.

In another aspect of this embodiment, the pellet has an elongated form.For example, the pellet may comprise a rod-shape dosage form that may besubstantially cylindrical.

In another aspect of this embodiment, the pellet is monolithic,comprising a substantially homogeneous matrix with the contraceptiveagent dispersed therein.

In another aspect of this embodiment, the pellet is composed of two ormore discrete regions each having a different composition, e.g.,compositions that differ with respect to components, component amount,component concentration, or the like. For example, the pellet may becomposed of two regions, with a first region containing thecontraceptive agent and the second region containing only inactiveingredients. As another example, the first region and the second regionmay both contain the same contraceptive agent but with the agent presentin different amounts and/or at different concentrations. As a furtherexample, the first and second regions may contain two differentcontraceptive agents.

In a related aspect, the pellet is composed of a core-and-shell type ofdosage form, where the first discrete region is the core and the seconddiscrete region is the shell. With an elongated dosage form, the firstregion may be an inner core having a length, a surface along the length,a first end, and a second end, and the second region may be an outershell enclosing the surface of the inner core along its length but notthe first end or the second end, such that the core has exposed surfacearea at the first and second ends. This type of structure may be onewherein: at least about 80 wt. % (e.g., at least about 90 wt. %,including 100%) of the contraceptive agent in the pellet is in the core(referred to herein as a “core-type” pellet); at least about 80 wt. %(e.g., at least about 90 wt. %, including 100%) of the contraceptiveagent in the pellet is in the shell (referred to herein as a“shell-type” pellet); or contraceptive agent is present in both the coreand the shell with greater than about 20 wt. % of the contraceptiveagent present in each region.

In another aspect of this embodiment, the extended drug delivery timeperiod includes an effective drug delivery time period, during which thecontraceptive agent is released at a dosage sufficient to providecontraceptive efficacy, where the effective drug delivery time period isin the range of about three months to about four years, e.g., about sixmonths to about four years; about six months to about three years; orabout one year to about three years, such as about 18 months.

In another aspect of this embodiment, the extended drug delivery timeperiod includes two time periods, a first time period that is aneffective drug delivery period as defined in the preceding paragraph,and a subsequent, second time period that is a sub-effective drugdelivery period during. That is, the pellet releases the contraceptiveagent during the first, “effective drug delivery period” at a dosagesufficient to provide contraceptive efficacy, but thereafter, during the“sub-effective drug delivery period,” the pellet continues to releasethe contraceptive agent but at a dosage that is less than sufficient toprovide contraceptive efficacy (where effective and sub-effectivedosages correlate with effective and sub-effect serum levels,respectively). The sub-effective drug delivery period, during which thepellet continues to release the active agent but at a dosage below aneffective contraceptive dosage, is sometimes referred to as a “tailperiod” and, in a preferred embodiment, is at most about 12 months. In arelated aspect of this embodiment, the tail period is at most about 9months.

In another embodiment, one or more aspects of the pharmacokineticprofile of the subdermally implantable pellet are selected and “tuned”during manufacture, using at least one pellet property selected fromwidth, length, diameter, surface area, size, composition, hardness, anddegree of crystallinity.

In a related aspect of this embodiment, the pellet includes a releaserate controlling agent as an excipient, wherein the release ratecontrolling agent has a water solubility effective to increase therelease rate of the active agent from the pellet or to decrease therelease rate of the active agent from the pellet, relative to therelease rate of the active agent from the pellet in the absence of therelease rate controlling agent.

In another related aspect of this embodiment, the pellet includes asoftening agent as an excipient. The selection of softening agent, theamount of the softening agent, or both, are selected so that the overallhardness of the pellet is as desired, e.g., for purposes ofimplantation, palpation, or the like. In a further related aspect ofthis embodiment, the softening agent is a crystallinity modulator.

In another embodiment of the invention, a method is provided foradministering a contraceptive agent to a female individual in asustained release manner over an extended drug delivery time period,where the method involves: providing a drug delivery system comprising asubdermally implantable, bioerodible pellet that continuously releases acontraceptive agent throughout an extended drug delivery time period;and subdermally implanting the drug delivery system into a femaleindividual. Products and by-products of pellet bioerosion dissolve orare resorbed, obviating the need for surgical removal.

In a related aspect of this embodiment, the method involves treatment ofa female individual having a condition, disease or disorder that isresponsive to the sustained release administration of the contraceptiveagent. In a further related aspect, the method comprises female hormonereplacement therapy.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 (PRIOR ART) is a graph showing the extended time period duringwhich an implanted norethindrone pellet was found to releasesub-effective but detectable concentrations of the active agent (adaptedfrom Raymond et al. (1996) Fertil. Steril. 66(6):954-61).

FIG. 2A schematically illustrates a pellet manufacturing assembly usedto make a monolithic pellet of the invention, prior to drawing thepellet composition into the pelleting tube; FIG. 2B schematicallyillustrates the pellet manufacturing assembly subsequent to drawing thepellet composition into the pelleting tube.

FIG. 3A schematically illustrates a pellet manufacturing assembly usedto make a core-and-shell type pellet of the invention; FIG. 3Billustrates the core-and-shell type pellet manufacturing assembly ofFIG. 3A with the shell composition having been introduced into thefunnel above the pelleting tube; FIG. 3C illustrates the core-and-shelltype pellet manufacturing assembly of FIG. 3B with the shell materialhas been drawn down into a concentric space within the pelleting tube;FIG. 3D illustrates the core-and-shell type pellet manufacturingassembly of FIG. 3C with the core composition having been introducedinto the funnel above the pelleting tube; and FIG. 3E illustrates thecore-and-shell type pellet manufacturing assembly of FIG. 3D with thecore composition having been drawn down into the cooled shell materialwithin the pelleting tube.

FIG. 4 provides the dissolution profiles for monolithic pellet implantswith different diameters, as described in Example 1.

FIG. 5 provides the dissolution profiles for monolithic pellet implantswith different lengths, as described in Example 2.

FIG. 6 provides the dissolution profile for core-type pellets, asdescribed in Examples 3 and 4.

FIG. 7 provides the dissolution profiles for shell-type pellets ofdifferent lengths, as described in Example 5.

FIG. 8A shows the dissolution profiles of thin monolithic pelletscompared with thick monolithic pellets, as also described in Example 5;FIG. 8B shows the dissolution profiles of core-type pellets comparedwith thick monolithic pellets, as also described in Example 5; FIG. 8Cshows the dissolution profiles of shell-type pellets compared with thickmonolithic pellets, as also described in Example 5.

FIGS. 9 through 12 illustrate the effect of active agent concentrationon release rate, in thick monolithic pellets (FIG. 9), thin monolithicpellets (FIG. 10), core-type pellets (FIG. 11), and shell-type pellets(FIG. 12), as described in Example 6.

FIGS. 13 through 17 illustrate the effect of excipient selection onrelease rate, as described in Example 7.

FIG. 18 illustrates the in vivo test results obtained in Example 8,showing plasma progestin levels measured at different post-implantationtime points.

FIG. 19 shows the correlation between total drug released and theexposed surface area of drug-containing regions within the pellet, asdetermined in Example 8, while FIG. 20 provides the AUC (mg*day/mL)versus amount of drug released.

DETAILED DESCRIPTION OF THE INVENTION I. Definitions and Terminology

Unless defined otherwise, all technical and scientific terms used hereinhave the meaning commonly understood by one of ordinary skill in the artto which the invention pertains. Specific terminology of particularimportance to the description of the present invention is defined below.

In this specification and the appended claims, the singular forms “a,”“an” and “the” include plural referents unless the context clearlydictates otherwise. Thus, for example, “a contraceptive agent” refersnot only to a single contraceptive agent but also to two or morecontraceptive agents that may or may not be combined in a mixture; “anexcipient” refers to a single excipient or two or more excipients,which, again, may or may not be combined in a mixture; and the like.

The term “bioerodible” is used herein in a manner synonymous with“biodegradable,” and includes any mechanism that may contribute to thegradual reduction in mass of an implanted pellet throughout an extendeddrug delivery period. Thus, a bioerodible pellet may degrade as a resultof in vivo forces interacting with the pellet surface such as shearforces; cellular action, e.g., endocytosis and cell-mediated dispersionof microscopic particles released from the pellet during cell migration;and gradual dissolution of one or more pellet components. Throughoutthis disclosure and claims, the use of the term “bioerodible” tocharacterize a subdermally implantable pellet of the invention alsoindicates that the pellet bioerodes in situ in a manner that obviatesthe need for surgical removal after completion of drug release (althoughearlier removal may sometimes be desirable for one reason or another),insofar as all pellet bioerosion products are either water soluble,bioresorbable, or both. Accordingly, the term “bioerodible,” in a firstinstance, refers to a completely bioerodible pellet, which may be, forexample, a pellet entirely composed of an active agent that is graduallyreleased in situ. In a second instance, and more typically, the term“bioerodible” refers to a pellet composed of a contraceptive agent andan excipient composition containing one or more excipients wherein eachexcipient is (a) a water-soluble and/or bioresorbable compound, or (b)transformed in situ to water-soluble or bioresorbable species, or (c)both (a) and (b), so that all products of pellet bioerosion aredissolved or absorbed within the body, and thus naturally and benignlycleared by the body.

The term “controlled release” refers to a drug-containing formulation ordosage form, e.g., subdermal implant, which does not result in immediaterelease of the drug into an absorption pool. The term is usedinterchangeably with “nonimmediate release” as defined in Remington: TheScience and Practice of Pharmacy, Nineteenth Ed. (Easton, Pa.: MackPublishing Company, 1995). “Controlled release” for the present purposeincludes “sustained release” (synonymous with “extended release”),referring to a formulation that provides for gradual release of anactive agent over an extended period of time.

The term “subdermal” to refer to the intended in situ location of theimplanted pellet means that the pellet is introduced at an interior bodylocation beneath the skin, where release of the active agent occursbeneath the skin and enters the systemic circulation, i.e., theimplantable pellets of the invention provide for “systemic” drugdelivery. Subdermal implantation includes subcutaneous implantation aswell as deeper implantation (the latter generally being the case withhormone replacement therapy, for example, wherein the implant istypically injected into the deeper fatty layers of the stomach orbuttocks rather than subcutaneously).

The term “lipophilic” as used herein refers to a pellet or to a pelletsegment (e.g., shell or core) containing less than 50 wt. % hydrophilicmaterials, where “hydrophilic” materials in this context are materialshaving an aqueous solubility greater than about 50 mg/mL (5 wt. %). Itwill be appreciated that a pellet, core, or shell that contains 50 wt. %or more of a lipophilic active agent is lipophilic as a result, even ifthe pellet, core, or shell contains one or more hydrophilic excipients,because the hydrophilic excipients necessarily represent less than 50wt. % of the pellet.

The term “water soluble” refers to a compound having an aqueoussolubility greater than about 30 mg/mL (i.e., 3 wt. %), typicallygreater than about 50 mg/mL (i.e. 5 wt. %).

A “lipidic material” refers to a composition comprising one or morelipidic compounds that in combination represent greater than 50 wt. % ofthe lipidic material, wherein “lipidic compounds” include lipids per se,i.e., naturally occurring lipids, whether obtained from a biologicalsource or chemically synthesized in whole or in part; lipid analogs;lipid derivatives; lipid conjugates; and the like.

The term “flowable” refers to a composition that has been transformed,by the application of heat and/or other means (e.g., formation of asuspension, slurry, or the like), from a solid or substantially solidform to a composition that flows. Normally, the transformation iseffected thermally, within the context of a hot melt manufacturingprocess, in which case the flowable composition so provided is alsoreferred to herein as “molten.” The approximate temperature at which apellet, shell, or core composition undergoes this transition is referredto herein as the “transition temperature.” The transition temperaturemay be seen as a melting temperature, although since the compositionsherein are usually mixtures, composed of two or more differentcompounds, there is no definite melting point (unless characterizedusing an empirical method such as the determination of dropping point orslip point).

The term “substantially homogeneous” indicates a material in the form ofa mixture of two or more components in which the material issubstantially uniform throughout, with any two discrete regions withinthe material differing by at most about 20%, preferably by at most about10%, and most preferably by at most about 5%, with respect to a chemicalor physical property of the material, such as the presence or absence ofa component, the concentration of a component, the degree ofhydrophilicity or lipophilicity, density, crystallinity, or the like.

“Pharmacologically active” (or simply “active”), as in a“pharmacologically active” analog, derivative or other version of anactive agent, refers to a compound having the same type ofpharmacological activity as the parent compound and approximatelyequivalent in degree. Therefore, when referring to a contraceptiveagent, whether specified as a particular compound (e.g., etonogestrel orlevonorgestrel) or a compound class (e.g., a progestogen or anestrogen), the term used is intended to encompass not only the specifiedmolecular entity or entities but also pharmaceutically acceptable,pharmacologically active analogs and derivatives thereof, including, butnot limited to, salts, esters, prodrugs, conjugates, active metabolites,crystalline forms, enantiomers, stereoisomers, and other suchderivatives, analogs, and related compounds.

In particular, as an example, when referring to a specific femalehormone, i.e., a progestogen or an estrogen, it is to be understood thatthe term not only refers to the agent per se in unmodified form, butalso refers to pharmacologically active, pharmaceutically acceptableesters of the agent. For instance, a reference to “hydroxyprogesterone”(17α-hydroxyprogesterone) includes not only hydroxyprogesterone per sebut also pharmacologically active, pharmaceutically acceptablehydroxyprogesterone esters such as hydroxyprogesterone caproate,hydroxyprogesterone acetate, and hydroxyprogesterone heptanoate.

It should also be noted, with regard to the contraceptive agent herein,that the “progestogen” can be progesterone, i.e., the naturallyoccurring progestogen, or it can be another naturally occurringprogestogen or a synthetic or semi-synthetic progestogen. Synthetic andsemi-synthetic progestogens are often referred to as “progestins.”Similarly, the term “an estrogenic compound” or “an estrogen” is usedherein to refer to naturally occurring estrogens as well as to syntheticand semi-synthetic estrogens.

The terms “effective amount” and “therapeutically effective amount” ofan agent, compound, or composition refer to an amount that is nontoxicand effective for the intended purpose, e.g., contraception, hormonereplacement therapy, or the like.

By “contraceptive efficacy” is meant contraceptive protection havingless than a 2% failure rate, preferably less than a 1% failure rate,less than a 0.5% failure rate, and less than a 0.25% failure rate, suchas a failure rate of 0.1% or lower.

The term “approximately” in any context is intended to connote apossible variation of at most about 20%. Generally, the term connotes apossible variation of at most about 10%, preferably at most about 5%.The term “substantially” is defined in an analogous manner.

An “excipient” herein refers to any component within the drug deliverysystem that is an inactive ingredient, such that all components otherthan the contraceptive agent are referred to herein as “excipients.” Anyexcipient used should be “pharmaceutically acceptable,” meaning notbiologically or otherwise undesirable, so that that the excipient can beincorporated into a dosage form administered to a patient withoutcausing any significant undesirable biological effects or interacting ina deleterious manner with any other components of the dosage form.“Pharmaceutically acceptable” excipients herein meet the criteria setout in the Inactive Ingredient prepared by the U.S. Food and DrugAdministration, and, preferably, have also been designated “GenerallyRegarded as Safe” (“GRAS”).

The terms “treating” and “treatment” as used herein refer to reductionin severity and/or frequency of symptoms, elimination of symptoms and/orunderlying cause, and improvement or remediation of damage, e.g.,reduction in the number and/or extent of menopausal symptoms with apatient being given hormone replacement therapy using the drug deliverysystem of the invention. Unless otherwise indicated, the terms“treating” and “treatment” as used herein encompass prevention ofsymptoms as well, for instance in the administration of hormonereplacement therapy to a perimenopausal woman.

As used herein, the terms “subject,” “individual,” and “patient” referto any female individual for whom the present contraceptive drugdelivery system is intended and to whom a contraceptive agent isadministered as described herein. The female individual may be human ora non-human animal, generally a mammal. Veterinary use of the presentdrug delivery system is thus envisioned.

II. Pellet Composition

The contraceptive drug delivery system of the invention is composed ofat least one subdermally implantable, bioerodible pellet that providesfor controlled, sustained release of a contraceptive agent containedtherein during an extended drug delivery time period. In one embodiment,each subdermally implantable pellet contains a single type ofcontraceptive agent, a progestogen; in a subset of this embodiment, theimplantable pellet contains a single progestogen. Suitable progestogensthat can be administered using the delivery system and method of theinvention include progesterone per se, i.e., the active naturalprogestogen that is found in the corpus luteum, placenta, and adrenalcortex. Other progestogens that can be effectively administered ascontraceptive agents using the presently disclosed system and method areother naturally occurring progestogens, synthetic progestogens, andsemi-synthetic progestogens; synthetic progestogens and semi-syntheticprogestogens are known in the art as “progestins.” Specific examples ofprogestogens useful in conjunction with the invention include, withoutlimitation, the following:

21-acetoxypregnenolone;

allylestrenol;

anagestone (17α-hydroxy-6α-methylpregn-4-en-20-one);

anagestone 17α-acetate;

chlormadinone;

chlormadinone 17α-acetate;

chloroethynyl norgestrel;

cyproterone;

cyproterone 17α-acetate;

desogestrel;

dienogest;

dimethisterone (6α,21-dimethylethisterone);

drospirenone (1,2-dihydrospirorenone);

ethisterone (17α-ethinyltestosterone or pregneninolone);

ethynerone;

etynodiol diacetate (norethindrol diacetate);

etonogestrel (11-methylene-levo-norgestrel; 3-keto-desogestrel);

gestodene;

hydroxyprogesterone (17α-hydroxyprogesterone);

hydroxyprogesterone caproate;

hydroxyprogesterone acetate;

hydroxyprogesterone heptanoate;

levonorgestrel;

lynestrenol;

medrogestone (6,17α-dimethyl-6-dehydroprogesterone);

medroxyprogesterone;

medroxyprogesterone acetate;

megestrol;

megestrol acetate;

segesterone acetate;

nomegestrol;

nomegestrol acetate;

norethindrone (norethisterone; 19-nor-17α-ethynyltestosterone);

norelgestromin (17-deacetylnorgestimate);

noretynodrel;

norgestrienone;

progesterone; and

retroprogesterone.

Progestogens within this group that are sometimes preferred include, byway of example only, desogestrel, dienogest, drospirenone, ethisterone,etonogestrel, gestodene, levonorgestrel, medroxyprogesterone, megestrol,norethindrone, norgestimate, and esters of any of the foregoing, whenthe compound allows for esterification (e.g., medroxyprogesteroneacetate, megestrol acetate, norethindrone acetate, etc.). Within theaforementioned group, the progestogenic agents that are particularlypreferred include etonogestrel and levonorgestrel.

In another embodiment, the contraceptive agent comprises a combination,e.g., a mixture, of a progestogen and an additional contraceptive agent.In this embodiment, the additional contraceptive agent is usually anestrogen, i.e., an estrogenic compound, with the ratio of theprogestogen to the estrogen selected to correspond to theprogestogen-to-estrogen ratios of commercially available dual hormonecontraceptive products, regardless of the mode of administration.Suitable estrogenic compounds will be known to those skilled in the artand are described in the literature, and include synthetic and naturalestrogens such as: estradiol (i.e., 1,3,5-estratriene-3,17β-diol, or“17β-estradiol”) and its esters, including estradiol benzoate, valerate,cypionate, heptanoate, decanoate, acetate and diacetate; 17α-estradiol;ethinylestradiol (i.e., 17α-ethinylestradiol) and esters and ethersthereof, including ethinylestradiol 3-acetate and ethinylestradiol3-benzoate; estriol and estriol succinate; polyestrol phosphate; estroneand its esters and derivatives, including estrone acetate, estronesulfate, and piperazine estrone sulfate; quinestrol; mestranol; andconjugated equine estrogens. Generally preferred such compounds include17β-estradiol, estetrol, estriol, estrone, ethinyl estradiol, mestranol,moxestrol, quinestrol, conjugated estrogens, and combinations thereof.

When any of the aforementioned progestogens are referred to withoutmention of a salt, ester, or other derivative or analog, it should againbe emphasized that reference to the active agent per se includes suchderivatives and analogs. Thus, when the term “cyproterone” is usedherein, the agent referred to may be cyproterone per se or a cyproteroneester such as cyproterone 17α-acetate, when the term“medroxyprogesterone” is used, the agent referred to may bemedroxyprogesterone per se or a medroxyprogesterone ester such asmedroxyprogesterone acetate, and the like.

The amount of the contraceptive agent in a drug delivery system of theinvention comprising a subdermally implantable pellet is selected toresult in serum levels of the contraceptive agent sufficient to providecontraceptive efficacy during the effective drug delivery time period,taking the release rate, length of the intended drug delivery timeperiod, and specific contraceptive agent into account. It should benoted that although the drug delivery system may be composed of only onesubdermally implantable pellet, it may also be composed of two to sixpellets, e.g., four or five pellets. When the drug delivery system iscomposed of more than one pellet, the number of pellets implanted isalso taken into account in determining the amount of contraceptive agentto incorporate into a single pellet. The optimum amount is preferablycalculated for a drug delivery time period in the range of about threemonths to about four years, e.g., in the range of about six months toabout four years; in the range of about six months to about three years;and in the range of about one year to about three years, for instanceabout 18 months. The total quantity of contraceptive agent in thesubdermally implanted drug delivery system for an approximately 18-monthdrug delivery time period, in the case of etonogestrel andlevonorgestrel, for example, will generally be in the range of about 5.0mg to about 200 mg, typically in the range of about 5.0 mg to about 50mg.

Drug loading may be in the range of about 20 wt. % to about 100 wt. %,preferably in the range of about 50 wt. % to about 99 wt. %, morepreferably in the range of about 75 wt. % to about 95 wt. %. Theaforementioned ranges pertain to the percentage of contraceptive agentin a monolithic pellet, or, for a core-type pellet or a shell-typepellet, the percentage of the contraceptive agent in the shell or core,respectively. Optimal drug loading may approximate 85 wt. %. The degreeof drug loading can be altered to vary drug release profile as desired.As shown in Example 7, increasing the fraction of contraceptive agent inthe pellet generally results in an increase in drug release rate.

The pellets may be wholly composed of active agent, but generally, andpreferably, contain an excipient composition as well, where theexcipient composition may be a single excipient or it may include two ormore excipients. Excipients for incorporation into the present pelletsalong with the active agent should be selected so as to avoidcompromising the bioerodibility of the pellet as a whole. This meansthat any excipients should be bioresorbable, water soluble, or both,and/or degrade or otherwise transform in situ, during bioerosion of thepellet, to bioresorbable and/or water-soluble species. Preferredexcipients are naturally occurring compounds, which may be obtained froma biological source or chemically synthesized in whole or in part. Oneor more excipients may be hydrophilic, providing that the pellet as awhole is still lipophilic. For core-type pellets and shell-type pellets,both the core and the shell should be lipophilic, meaning that the coreand shell each contain less than 50 wt. % hydrophilic materials,preferably less than 45 wt %, less than 40 wt. %, less than 35 wt. %,less than 30 wt. %, less than 25 wt. %, less than 20 wt. %, less than 15wt. %, less than 10 wt. %, or less than 5 wt. % of the pellet.“Hydrophilic” materials, as noted previously, are materials having anaqueous solubility of at least about 3 wt. %, e.g., at least about 5 wt.%, or the like. For example, a pellet, core, or shell that contains alipophilic active agent, with the lipophilic active agent representingat least 50 wt. % of the pellet, core, or shell, respectively, isnecessarily lipophilic, insofar as the total hydrophilic componentsrepresent less than 50 wt. % of the pellet, core, or shell composition.

Excipients may or may not be solid at body temperature and under storageconditions, so long as: (1) the pellet as a whole is substantially solidat body temperature and during storage, i.e., at temperatures in therange of about 35° C. to about 40° C.; and (2) the pellet composition isflowable at a selected temperature in the range of about 50° C. to about250° C., particularly when a hot melt manufacturing technique—such asthe manufacturing process described herein—is used. In addition,excipients should be selected so that the pellet does not fracture orbreak during or after implantation. This may require inclusion of asoftening agent as an excipient, e.g., lecithin. However, the pelletshould still be hard enough so that it can be palpated afterimplantation, to confirm or determine location.

Suitable excipients include, but are not limited to, lipidic compounds,e.g., lipids per se, including naturally occurring lipids and lipidsthat are chemically synthesized in whole or in part; lipid analogs;lipid derivatives; lipid conjugates; and the like. Naturally occurringlipids and readily hydrolyzable esters of naturally occurring lipids aregenerally preferred lipidic excipients, insofar as such compoundsfacilitate bioabsorption and bioerosion to nontoxic molecularcomponents. For example, a lipidic excipient may be a sterol, a sterolester, or a combination thereof, including, without limitation,cholesterol, 7-dehydrocholesterol, cholestatrienol, cholestanol,cholesteryl acetate, desmosterol, dehydroergosterol, thiocholesterol,3-keto-delta-5-cholestene, 7-methylenecholesterol, epicholesterol,lathosterol, lanosterol, dihydrocholesterol, 25-hydroxycholesterol,cholestane, cholestane diol, cholest-4-en-3-one, and zymosterol. In someembodiments, cholesterol is a preferred lipidic excipient herein.

Other lipidic compounds that can serve as excipients herein include, butare not limited to, the following: phospholipids such as phosphorylateddiacyl glycerides, particularly phospholipids selected from the groupconsisting of diacyl phosphatidylcholines, diacylphosphatidylethanolamines, diacyl phosphatidylserines, diacylphosphatidylinositols, diacyl phosphatidylglycerols, diacyl phosphatidicacids, and mixtures thereof, wherein each acyl group contains about 10to about 22 carbon atoms and is saturated or unsaturated; fatty acidssuch as isovaleric acid, valeric acid, caproic acid, enanthic acid,caprylic acid, pelargonic acid, capric acid, lauric acid, myristic acid,palmitic acid, stearic acid, arachidic acid, behenic acid, lignocericacid, oleic acid, linoleic acid, linolenic acid, and arachidonic acid;lower fatty acid esters comprising esters of the foregoing fatty acids,wherein the carboxylic acid group of the fatty acid is replaced with anester moiety —(CO)—OR wherein R is a C₁-C₃ alkyl moiety optionallysubstituted with one or two hydroxyl groups; fatty alcoholscorresponding to the aforementioned fatty acids, wherein the carboxylicacid group of the fatty acid is replaced by a —CH₂OH group; glycolipidssuch as cerebroside and gangliosides; oils, including animal oils suchas cod liver oil and menhaden oil, and vegetable oils such as babassuoil, castor oil, corn oil, cottonseed oil, linseed oil, mustard oil,olive oil, palm oil, palm kernel oil, peanut oil, poppyseed oil,rapeseed oil, safflower oil, sesame oil, soybean oil, sunflower seedoil, tung oil, or wheat germ oil; and waxes, i.e., higher fatty acidesters, including animal waxes such as beeswax and shellac, mineralwaxes such as montan, petroleum waxes such as microcrystalline wax andparaffin, and vegetable waxes such as carnauba wax.

A lipidic excipient may also be incorporated into the pellets in acombination or mixture of two or more excipients (including mixtures oftwo or more lipidic excipients), for example having different aqueoussolubilities and/or with one of the excipients selected to serve aparticular purpose (e.g., functioning as a softening agent). Forexample, a pellet may contain a combination of a lipidic excipienthaving a first aqueous solubility and a second excipient, which may ormay not be lipidic, having a second aqueous solubility, where the firstaqueous solubility is lower than the second aqueous solubility by atleast 5%, typically by at least 10%. The weight ratio of the lesssoluble excipient to the more soluble excipient may be in the range ofabout 2:1 to about 100:1, more typically in the range of about 3:1 toabout 50:1, and optimally about 3.5:1 to about 25:1, e.g., 4:1. Theexamples herein describe such excipient compositions, whereincholesterol serves as the lipidic excipient with a first aqueoussolubility and lecithin or a component thereof (e.g.,phosphatidylcholine) serves as the second excipient.

Additional excipients that can be incorporated into the pellets insteadof, or in addition to, a lipidic excipient as described above, include,without limitation, phospholipids and phospholipid mixtures, e.g.,lecithin (a phospholipid mixture) and glycerophospholipids such asphosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, andphosphatidylserine; polyethylene glycols (PEGs) of different molecularweights, e.g., PEG-300, PEG-1000, PEG-4000, PEG-6000, and PEG-8000; PEGfatty acid esters such as PEG laurates, oleates, stearates, and thelike; other gradually erodible synthetic polymers such as polylactides,polyglycolides, polycaprolactones, polyanhydrides, polyurethanes,polyesteramides, polyorthoesters, polyvinylpyrrolidone, andpolyhydroxycellulose; polymers typically used to prepare hydrogels,e.g., polyvinyl alcohol, poly(hydroxyethyl methacrylate), andpolyacrylic acid; glycerine and glycerinated gelatin; chitin andchitosan; and lower molecular weight excipients such as propyleneglycol.

If desired, a radio-opaque material can be incorporated into the presentdrug delivery systems in order to enable X-ray visualization of theimplanted pellets. Suitable radio-opaque materials for this purpose areknown in the art and include, for instance, barium sulfate, titaniumoxide, bismuth oxide, tungsten, and iodinated contrast agents (i.e.,contrast based on the 2,4,6-triiodobenzene structure), with bariumsulfate more commonly used. Any such radio-opaque material willgenerally represent in the range of about 2.5 wt. % to about 30 wt. % ofa pellet, more typically about 2.5 wt. % to about 15 wt. % of a pellet.

III. Physical and Pharmacokinetic Attributes of the Pellet

The pellets herein can be of any size, shape or structure that allow forease of manufacture and implantation, and that contribute to or at leastdo not detract from the desired pharmacokinetic properties. Generally,for ease of manufacture and implantation, the pellets are rod-shaped,i.e., approximately cylindrical, with length, width, surface area, etc.,selected to provide specific pharmacokinetic or other properties, suchas drug release rate, drug release profile (i.e., the change in releaserate over time), length of the effective drug delivery period, length ofany tail period, and the like.

An elongated pellet of the invention may be substantially cylindrical.Such pellets will generally have a length in the range of about 2.0 mmto about 12.0 mm, and a diameter in the range of about 1.0 mm to about3.5 mm. Typically, pellet length is in the range of about 3.5 mm toabout 7.0 mm, with pellet diameter in the range of about 1.0 to about3.2. In a preferred embodiment, the pellet length is in the range ofabout 4.0 mm to about 6.5 mm and the pellet diameter is in the range ofabout 1.3 mm to about 3.0 mm. Exemplary pellet dimensions thus include:diameter 2.8 mm, length 6.0 mm; diameter 2.8 mm, length 4.5 mm; diameter2.8 mm, length 4.0 mm; diameter 1.7 mm, length 4.0 mm. Additionalexamples are given below.

In one embodiment, the pellet is monolithic, such that the pellet iscomprised of a substantially homogeneous matrix with the contraceptiveagent is dispersed therein, where “substantially homogeneous” is definedin Part (I) of this section. In such a case, the pellet may beessentially amorphous, or it may be crystalline or partiallycrystalline, preferably without any interior voids. To check amonolithic pellet for substantial homogeneity, the pellet can be dividedinto several, e.g., three to six, subsections, and each subsectionweighed and dissolved in a known amount of solvent. Each dissolvedsubsection can then be analyzed using a standard technique, e.g., HPLC,and the relative quantities of components determined and compared to theresults in the other subsections.

A standard monolithic pellet will have dimensions as described above.

Monolithic pellets generally have a density in the range of about 0.75g/cm³ to about 1.25 g/cm³, as do pellets composed of two or morediscrete regions, e.g., cores and shells in core-type and shell-typepellets herein. More typically, monolithic pellets typically have adensity in the range of about 0.90 g/cm³ to about 1.10 g/cm³, and mosttypically in the range of about 0.95 g/cm³ to about 1.05 g/cm³.

In another embodiment, the pellet is composed of two or more discreteregions each having a different composition. That is, compositions indifferent regions may differ with respect to components of thecomposition, component amount, component concentration, or the like. Forexample, the pellet may be composed of a first region containing thecontraceptive agent and a second region containing only inactiveingredients, i.e., excipients. As another example, the first and secondregion may contain the same contraceptive agent, but in differentamounts and/or present at different concentrations. Discrete regions mayalso contain different active agents, including different contraceptiveagents.

A preferred pellet structure composed of two or more discrete regions isa core-and-shell type of dosage form, where the first region is an innercore and the second region is a shell that partially or entirelyencloses the core. With an elongated dosage form such as a cylindricalpellet, the first region may be an inner core having a length, a surfacealong the length, a first end, and a second end, and the second regionmay be an outer shell enclosing the surface of the inner core along itslength but not the first end or the second end, such that the core hasexposed surface area at the first and second ends. This type ofstructure may be one wherein: at least about 80 wt. %, e.g., at leastabout 90 wt. %, of the contraceptive agent in the pellet is in the core(a “core-type” pellet); at least about 80 wt. %, e.g., at least about 90wt. %, of the contraceptive agent in the pellet is in the shell (a“shell-type” pellet); or contraceptive agent is present in both the coreand the shell with greater than about 20 wt. %, e.g., greater than about10 wt. %, of the contraceptive agent present in each region. In oneembodiment, a core-type pellet is composed of an inactive shell with100% of the contraceptive agent in the core. In another embodiment, ashell-type pellet is composed of an inactive core with 100% of thecontraceptive agent in the shell.

Typical dimensions for core-shell structures, including core diameterand shell thickness, are as follows: core diameter, about 1.0 mm toabout 2.0 mm, shell thickness about 0.3 mm to about 1.0 mm, and lengthabout 4 mm to about 6.5 mm. Specific examples of core/shell structuredimensions include, without limitation: core diameter 1.7 mm, shellthickness 0.6 mm, length 4.5 mm; core diameter 1.9 mm, shell thickness0.9 mm, length 4.5 mm; core diameter 1.7 mm, shell thickness 0.6 mm,length 5.5 mm; and core diameter 1.9 mm, shell thickness 0.9 mm, length5.5 mm.

The inactive region of a core-type pellet or a shell-type pellet,whether shell or core, is composed of a bioerodible excipientcomposition as described earlier herein, with the inactive regioncontaining less than about 20 wt. %, e.g., less than about 10 wt. %, ofthe total amount of contraceptive agent in the pellet. Thepharmacologically active region of a core-type pellet or a shell-typepellet, i.e., the region containing at least about 80 wt. %, e.g., atleast about 90 wt. % of the total amount of contraceptive agent in thepellet, may be entirely composed of the contraceptive agent, but isusually a mixture of a bioerodible excipient composition, as definedpreviously, and the contraceptive agent, where the contraceptive agentis dispersed within a matrix defined by the bioerodible excipientcomposition. The excipient composition of the inactive region and theexcipient composition of the pharmacologically active region may or maynot be the same, with respect to the number, type, and/or concentrationof individual excipients.

Representative examples of shell and core drug delivery systems of theinvention include, without limitation, the following:

Monolithic pellets 1.7 mm in diameter and 4.0 mm in length, containing85 wt. % etonogestrel;

Monolithic pellets 1.7 mm in diameter and 4.0 mm in length, containing85 wt. % levonorgestrel;

Monolithic pellets 1.7 mm in diameter and 4.0 mm in length, containing85 wt. % desogestrel;

Monolithic pellets 1.7 mm in diameter and 4.5 mm in length, containing95 wt. % etonogestrel;

Monolithic pellets 1.7 mm in diameter and 4.5 mm in length, containing95 wt. % levonorgestrel;

Monolithic pellets 1.7 mm in diameter and 4.5 mm in length, containing95 wt. % desogestrel;

Monolithic pellets 1.7 mm in diameter and 3.5 mm in length, containing75 wt. % etonogestrel;

Monolithic pellets 1.7 mm in diameter and 3.5 mm in length, containing75 wt. % levonorgestrel;

Monolithic pellets 1.7 mm in diameter and 3.5 mm in length, containing75 wt. % desogestrel;

Monolithic pellets 2.8 mm in diameter and 5.5 mm in length, containing85 wt. % etonogestrel;

Monolithic pellets 2.8 mm in diameter and 5.5 mm in length, containing85 wt. % levonorgestrel;

Monolithic pellets 2.8 mm in diameter and 5.5 mm in length, containing85 wt. % desogestrel;

Monolithic pellets 2.8 mm in diameter and 6.0 mm in length, containing95 wt. % etonogestrel;

Monolithic pellets 2.8 mm in diameter and 6.0 mm in length, containing95 wt. % levonorgestrel;

Monolithic pellets 2.8 mm in diameter and 6.0 mm in length, containing95 wt. % desogestrel;

Monolithic pellets 2.8 mm in diameter and 5.5 mm in length, containing75 wt. % etonogestrel;

Monolithic pellets 2.8 mm in diameter and 5.5 mm in length, containing75 wt. % levonorgestrel;

Monolithic pellets 2.8 mm in diameter and 5.5 mm in length, containing75 wt. % desogestrel;

Monolithic pellets 2.8 mm in diameter and 4.5 mm in length, containing85 wt. % etonogestrel;

Monolithic pellets 2.8 mm in diameter and 4.5 mm in length, containing85 wt. % levonorgestrel;

Monolithic pellets 2.8 mm in diameter and 4.5 mm in length, containing85 wt. % desogestrel;

Monolithic pellets 2.8 mm in diameter and 4.0 mm in length, containing75 wt. % etonogestrel;

Monolithic pellets 2.8 mm in diameter and 4.0 mm in length, containing75 wt. % levonorgestrel; and

Monolithic pellets 2.8 mm in diameter and 4.0 mm in length, containing75 wt. % desogestrel.

Shell/core pellets with a core 1.6 mm in diameter, a shell 0.6 mm inthickness, and the pellet 5.5 mm in length, with the shell composed of85 wt. % etonogestrel, 12 wt. % cholesterol, and 3 wt. %phosphatidylcholine, and the core composed of 97 wt. % cholesterol and 3wt. % phosphatidylcholine;

Shell/core pellets with a core 1.6 mm in diameter, a shell 0.6 mm inthickness, and the pellet 5.5 mm in length, with the shell composed of85 wt. % levonorgestrel, 12 wt. % cholesterol, and 3 wt. %phosphatidylcholine, and the core composed of 97 wt. % cholesterol and 3wt. % phosphatidylcholine;

Shell/core pellets with a core 1.6 mm in diameter, a shell 0.6 mm inthickness, and the pellet 5.5 mm in length, with the shell composed of85 wt. % desogestrel, 12 wt. % cholesterol, and 3 wt. %phosphatidylcholine, and the core composed of 97 wt. % cholesterol and 3wt. % phosphatidylcholine;

Shell/core pellets with a core 1.6 mm in diameter, a shell 0.6 mm inthickness, and the pellet 5.0 mm in length, with the shell composed of85 wt. % etonogestrel, 12 wt. % cholesterol, and 3 wt. %phosphatidylcholine, and the core composed of 97 wt. % cholesterol and 3wt. % phosphatidylcholine;

Shell/core pellets with a core 1.6 mm in diameter, a shell 0.6 mm inthickness, and the pellet 5.0 mm in length, with the shell composed of85 wt. % levonorgestrel, 12 wt. % cholesterol, and 3 wt. %phosphatidylcholine, and the core composed of 97 wt. % cholesterol and 3wt. % phosphatidylcholine;

Shell/core pellets with a core 1.6 mm in diameter, a shell 0.6 mm inthickness, and the pellet 5.0 mm in length, with the shell composed of85 wt. % desogestrel, 12 wt. % cholesterol, and 3 wt. %phosphatidylcholine, and the core composed of 97 wt. % cholesterol and 3wt. % phosphatidylcholine;

Shell/core pellets with a core 1.6 mm in diameter, a shell 0.6 mm inthickness, and the pellet 4.5 mm in length, with the shell composed of85 wt. % etonogestrel, 12 wt. % cholesterol, and 3 wt. %phosphatidylcholine, and the core composed of 97 wt. % cholesterol and 3wt. % phosphatidylcholine;

Shell/core pellets with a core 1.6 mm in diameter, a shell 0.6 mm inthickness, and the pellet 4.5 mm in length, with the shell composed of85 wt. % levonorgestrel, 12 wt. % cholesterol, and 3 wt. %phosphatidylcholine, and the core composed of 97 wt. % cholesterol and 3wt. % phosphatidylcholine;

Shell/core pellets with a core 1.6 mm in diameter, a shell 0.6 mm inthickness, and the pellet 4.5 mm in length, with the shell composed of85 wt. % desogestrel, 12 wt. % cholesterol, and 3 wt. %phosphatidylcholine, and the core composed of 97 wt. % cholesterol and 3wt. % phosphatidylcholine;

Shell/core pellets with a core 1.6 mm in diameter, a shell 0.6 mm inthickness, and the pellet 6.0 mm in length, with the shell composed of85 wt. % etonogestrel, 12 wt. % cholesterol, and 3 wt. %phosphatidylcholine, and the core composed of 97 wt. % cholesterol and 3wt. % phosphatidylcholine;

Shell/core pellets with a core 1.6 mm in diameter, a shell 0.6 mm inthickness, and the pellet 6.0 mm in length, with the shell composed of85 wt. % levonorgestrel, 12 wt. % cholesterol, and 3 wt. %phosphatidylcholine, and the core composed of 97 wt. % cholesterol and 3wt. % phosphatidylcholine;

Shell/core pellets with a core 1.6 mm in diameter, a shell 0.6 mm inthickness, and the pellet 6.0 mm in length, with the shell composed of85 wt. % desogestrel, 12 wt. % cholesterol, and 3 wt. %phosphatidylcholine, and the core composed of 97 wt. % cholesterol and 3wt. % phosphatidylcholine;

Shell/core pellets with a core 1.6 mm in diameter, a shell 0.6 mm inthickness, and the pellet 4.5 mm in length, with the core composed of 85wt. % etonogestrel, 12 wt. % cholesterol, and 3 wt. %phosphatidylcholine, and the shell composed of 97 wt. % cholesterol and3 wt. % phosphatidylcholine;

Shell/core pellets with a core 1.6 mm in diameter, a shell 0.6 mm inthickness, and the pellet 4.5 mm in length, with the core composed of 85wt. % levonorgestrel, 12 wt. % cholesterol, and 3 wt. %phosphatidylcholine, and the shell composed of 97 wt. % cholesterol and3 wt. % phosphatidylcholine;

Shell/core pellets with a core 1.6 mm in diameter, a shell 0.6 mm inthickness, and the pellet 4.5 mm in length, with the core composed of 85wt. % desogestrel, 12 wt. % cholesterol, and 3 wt. %phosphatidylcholine, and the shell composed of 97 wt. % cholesterol and3 wt. % phosphatidylcholine;

Shell/core pellets with a core 1.6 mm in diameter, a shell 0.6 mm inthickness, and the pellet 4.0 mm in length, with the core composed of 85wt. % etonogestrel, 12 wt. % cholesterol, and 3 wt. %phosphatidylcholine, and the shell composed of 97 wt. % cholesterol and3 wt. % phosphatidylcholine;

Shell/core pellets with a core 1.6 mm in diameter, a shell 0.6 mm inthickness, and the pellet 4.0 mm in length, with the core composed of 85wt. % levonorgestrel, 12 wt. % cholesterol, and 3 wt. %phosphatidylcholine, and the shell composed of 97 wt. % cholesterol and3 wt. % phosphatidylcholine;

Shell/core pellets with a core 1.6 mm in diameter, a shell 0.6 mm inthickness, and the pellet 4.0 mm in length, with the core composed of 85wt. % desogestrel, 12 wt. % cholesterol, and 3 wt. %phosphatidylcholine, and the shell composed of 97 wt. % cholesterol and3 wt. % phosphatidylcholine;

Shell/core pellets with a core 1.6 mm in diameter, a shell 0.6 mm inthickness, and the pellet 5.0 mm in length, with the core composed of 85wt. % etonogestrel, 12 wt. % cholesterol, and 3 wt. %phosphatidylcholine, and the shell composed of 97 wt. % cholesterol and3 wt. % phosphatidylcholine;

Shell/core pellets with a core 1.6 mm in diameter, a shell 0.6 mm inthickness, and the pellet 5.0 mm in length, with the core composed of 85wt. % levonorgestrel, 12 wt. % cholesterol, and 3 wt. %phosphatidylcholine, and the shell composed of 97 wt. % cholesterol and3 wt. % phosphatidylcholine; and

Shell/core pellets with a core 1.6 mm in diameter, a shell 0.6 mm inthickness, and the pellet 5.0 mm in length, with the core composed of 85wt. % desogestrel, 12 wt. % cholesterol, and 3 wt. %phosphatidylcholine, and the shell composed of 97 wt. % cholesterol and3 wt. % phosphatidylcholine.

In one embodiment, the tail period is at most about 12 months,preferably at most about 9 months, more preferably at most about 6months, and ideally at most about 3 months. This contrasts with tailperiods observed with prior implants, such as those described by Raymondet al. (1996) Fertil. Steril. 66(6):954-61), illustrated in FIG. 1(prior art).

Various parameters can be adjusted to alter one or more other aspects ofa pellet's pharmacokinetic profile, such aspects including, by way ofexample, release rate, release profile, duration of the extended drugdelivery time period, and duration of the tail period. For instance, therate of drug release can be controlled both by modulating the aqueoussolubility of the pellet composition and by controlling the surface areaof the pellet, as it is the pellet surface that is exposed to in vivoerosive forces. With monolithic implants, narrower and longer pelletsgenerally have a shorter tail period. Monolithic thin pellets withlength-to-width ratios (i.e., length-to-radius ratios for substantiallycylindrical pellets) greater than about 5:1 provide for a gradual,evenly decreasing release rate. The release rate of contraceptive agentfrom a monolithic pellet can be controlled by the bioerosion rate of theexcipient composition, made tunable using excipients with differentaqueous solubilities, as alluded to earlier herein. That is, anexcipient composition composed entirely of a lipidic material such ascholesterol will tend to bioerode more slowly than an excipientcomposition composed of a mixture of cholesterol and a second excipienthaving higher aqueous solubility, e.g., a selected phospholipid. Therate of release can thus be controlled by varying the relative amountsof a more water-soluble excipient and a less water-soluble excipient inan excipient composition.

For substantially cylindrical core/shell pellets composed of a slowlydissolving core and a more quickly dissolving shell that contains mostor all of the contraceptive agent, the drug release profile abruptlyends as erosion from the lateral face breaks through to the underlyingcore. Unlike monolithic pellets, the exposed surface area of thedrug-containing shell approaches a non-zero value as it bioerodes, thusavoiding the release tail. In these drug-containing shell pellets, therate of drug release is controlled by the rate of shell bioerosion andby the pellet length. The duration of drug release is controlled by theshell thickness.

Placing the contraceptive agent in the core instead of the shell canalso eliminate the tail if the rate of core erosion is significantlyfaster than that of the shell. Here, the exposed drug-containing surfaceis only at the cylinder bases and drug release remains relativelyconstant until the core erodes out of the longer-lasting shell. Theshell and core release rates are tuned with the proper addition of alipid with higher aqueous solubility than cholesterol per se, so thaterosion from the lateral face of the shell does not allow breakthroughbefore the pellet core is fully released. To achieve this result, theshell thickness divided by the shell erosion rate must be greater thanor equal to the core length divided by the core erosion rate. In thesedrug-containing core systems, the rate of drug release is dependent uponthe rate of core dissolution and the surface area of the core bases, andthe duration of release is controlled by the pellet length. Anadditional benefit of a drug-containing core can be approximatelyzero-order drug release.

IV. Contraceptive Method

At the outset, the number of pellets to be implanted is determined,taking into account the particular contraceptive agent, thepredetermined release rate, the intended drug delivery time period, andother factors within the knowledge of the medical practitionerprescribing or administering the contraceptive system.

The pellet or pellets are then subdermally implanted, usually in theupper arm, forearm, or thigh, and allowed to remain in place. Since thepellets are bioerodible, there is no need for surgical removal, althoughthe pellets can be surgically removed, if desired, at some point priorto complete bioerosion.

V. Other Methods of Use

The bioerodible, implantable pellets of the invention are also useful inproviding controlled release delivery of a contraceptive agent to femaleindividuals for purposes unrelated to contraception. For instance, thepresent drug delivery systems are useful in providing female hormonereplacement therapy (“HRT”), in that the occurrence of symptoms orconditions resulting from a woman's altered hormone levels is mitigatedor substantially prevented. HRT is useful to treat women for whomovarian steroid production has been altered, either because ofmenopause, surgery, radiation treatment, or premature ovarian failure.The subdermally implantable pellets of the invention are also useful inproviding for the ongoing, controlled release of a contraceptive agentto a female individual in need of such treatment for other reasons,e.g., treatment or prevention of osteoporosis, treatment of certainneurodegenerative diseases, treatment of mood disorders, and the like.Other conditions, disorders, and diseases that may be treatable usingthe drug delivery systems of the invention will be known to those ofordinary skill in the art and/or are described in the relevant texts andliterature.

VI. Pellet Implantation

One or more controlled release contraceptive pellets of the inventionare subdermally implanted into a patient for long-term, sustainedrelease administration of the contraceptive agent therein, as describedthroughout this specification. Generally, although not necessarily, thedrug-containing pellets are positioned just under the skin. Methods anddevices for insertion and positioning of subdermal implants are known inthe art, and any suitable method or device can be used in conjunctionwith the invention. Examples of suitable implantation devices includetrocar-like inserters, other commercially available implantationdevices, and devices described in the patent literature such as in U.S.Pat. Nos. 4,223,674; 6,964,648; 7,214,206; 7,510,549; 7,850,639; andInternational Patent Publication No. WO 98/13092 A1. Other suitableimplantation devices will be apparent to those skilled in the art and/orare described in pertinent texts and literature. Subdermal implantationmethods and devices should be non-irritating and non-sensitizing, andshould work relatively quickly.

VII. Pellet Manufacture

Any method to manufacture the present pellets can be used so long as thecompositional and physical requirements of the pellets so made are met.Manufacturing methods include, for example, compression molding,molding, hot melt extrusion, injection molding, and hot melt molding.

One example of a preferred method to manufacture the present pellets isa variation of the hot melt molding process, a hot melt “drawing”process that uses a pin to pull a substantially homogenous mixture ofpellet substrate material out of a heated reservoir and into a heatedchannel, or tube, composed of an inert, heat-resistant material such aspolytetrafluoroethylene (“PTFE”). The pellet material can then be cooledunder “channel capping” conditions, i.e., conditions that allow thepellet to fully form without internal cavities or sinks. Channel cappinginvolves withdrawal of the elongated pin from the interior of the formedpellet, when still warm, in a gradual manner that allows the interior ofthe pellet to fuse and contract.

The method can be modified to make core-type and shell-type pellets, byfirst drawing molten shell material from the reservoir into the channeland allowing it to harden somewhat, forming a shell between a narrow pinextension and the interior of the channel. After allowing some cooling,and wiping the reservoir clean before continuing, molten core materialfrom the reservoir is then drawn into the solidified shell. After abrief cooling period, the solid core-and-shell pellet can be pushed outof the channel/tube.

FIGS. 2A and 2B illustrate a pellet manufacturing assembly that can beused to make monolithic pellets of the invention. As shown in FIG. 2A,the assembly 10 includes an elongated pin having a body 12, a tip 14,and a substantially cylindrical upper segment 16. The pin is used inconjunction with pelleting tube 18, which has an upper tube opening 20,an opposing lower tube opening 22, and an inner surface. Tube 18 has aninner diameter sized to provide a sealing fit between the inner surfaceand the upper segment of the pin. The assembly further includes a funnel24 in the form of an inverted cone structure concentrically taperingfrom an upper rim 26 down to a narrow outlet 28 aligned with the uppertube opening 20. It will be appreciated that the a functionallyequivalent reservoir can be substituted for the funnel, providing thatthe reservoir is large enough to contain the intended volume of theselected pellet composition and has an outlet that enables downward flowof the pellet composition in a molten state. The funnel and tube aretherefore in fluid communication so that the flowable pelleting materialcan enter the tube from the funnel.

To manufacture a pellet, the pin tip 14 is inserted into tube 18 throughlower tube opening 22, and the pin is then moved upward through the tubetoward the funnel until the pin tip reaches the upper tube opening; thepin is shown positioned in this manner in FIG. 2A. At that point, theupper tube opening having been sealed with the upper segment of the pin,the pellet composition 30, containing a pharmacologically active agent,is placed into the funnel. The pellet composition may be placed into thefunnel in molten, i.e., flowable, form, or it can be heated within thefunnel until rendered flowable if a temperature control mechanism isoperably connected to the funnel body. The pin is then partiallywithdrawn from the tube through the lower tube opening, such that thepin tip is lowered a selected distance 32 from the upper tube opening,as illustrated in FIG. 2B. This draws the molten pellet composition 30down into the tube via a siphoning effect. After the pin tip has beenlowered, the pellet composition is allowed to cool so as to form thehardened pellet within the tube. The pin is then completely removed fromthe tube, and the pellet removed using any suitable means. The pellet soformed has a pellet length corresponding to the distance that the pintip is lowered, i.e., the “selected distance,” and a pellet diameterdefined by the inner diameter of the pelleting tube. In a preferredembodiment, the assembly includes a means for maintaining the pelletingtube in place, such as the collar 34 shown in FIGS. 2A and 2B.

To form a core-and-shell type of pellet, illustrated in FIGS. 3A through3E, a pellet manufacturing assembly 36 includes a pelleting tube 38 anda funnel 40 as described above for monolith manufacture. In this case,however, an elongated pin 42 is used that is composed of two axiallyaligned, substantially cylindrical segments of different diameters thatare longitudinally adjacent, with a wider lower segment 44 and anarrower upper segment 46 that terminates in the pin tip 48. Inaddition, the relative dimensions in this context are such that asealing fit is provided between the inner surface of the tube and thewider, lower segment of the elongated pin, while, as indicated in FIG.3A, the upper, narrower segment of the pin is significantly narrowerthan the inner diameter of the tube.

Formation of a core-and-shell pellet begins by inserting the pin tipinto the lower tube opening and moving the pin upward through the tube,toward the funnel, until the pin tip and then the upper pin segmentprotrude from the upper tube opening into the funnel; this configurationis shown in FIG. 3A. Upward, vertical movement of the pin through thetube in this way brings the lower pin segment into the tube, with theupper tube opening sealed as a result. As the shell is made first, theshell composition 50 is then placed into the funnel; see FIG. 3B. Aswith monolith manufacture, the shell composition may be heated untilrendered flowable prior to placement in the funnel, or it can be heatedwithin the funnel if a suitable heating apparatus is operably connected.To make the shell, the lower pin segment is gradually withdrawn from thetube through the lower tube opening, thus lowering the upper pin segmentinto the tube and simultaneously drawing the flowable shell compositioninto the concentric space forming between the upper, narrow segment ofthe pin and the inner surface of the tube as the pin is lowered; seeFIG. 3C. The hot shell composition is allowed to cool, thereby hardeninginto a shell 52 formed around the upper segment of the pin, within thetube, as shown in FIG. 3C.

The core composition 54 (see FIG. 3D) is added into to the funnel 40after cleaning, and is either in molten, flowable form prior toplacement in the funnel or heated therein, as described above. Thenarrower, upper pin segment 46 is then gradually lowered within thetube, drawing the core composition down into the shell; see FIG. 3E. Thecore-and-shell pellet so formed is allowed to cool, with the molten core56 fusing within the shell 52 during the cooling process, and harden toa degree sufficient to allow complete removal of the pin without anyflow of pelleting material. The finished pellet can then be removed fromthe tube using any suitable means.

The methodology allows facile control over pellet dimensions, insofar asthe diameter of the pellet formed is determined by the inner diameter ofthe tube, and the length of the pellet is determined by the extent towhich the pin or individual segments thereof are lowered within thetube, before the pellet, core, or shell is allowed to cool and harden.It will therefore be appreciated that the method can be readily adaptedto make pellets of different dimensions. That is, pellets of differentdiameters can be made by using a narrower or wider tube, and,correspondingly, different core diameters, while pellet length can beadjusted by lowering the pin within the tube to a lesser or greaterdegree as molten pellet material is drawn into the tube interior.

The above-described process for making core-and-shell pellets can beadapted to make pellets with more than one shell, by using an elongatedpin with multiple segments and segment-by-segment step-wise lowering ofthe pin within the tube, as each shell is made and allowed to hardenwithin the pelleting tube.

Channel capping, as explained earlier in this section, facilitatespellet formation in a manner that allows the interior pellet to fuse andcontract without formation of internal cavities or sinks. This is done,in part, by lowering the pin within the tube in a gradual manner, and inpart by allowing a small amount of pelleting composition to remain inthe funnel just above the funnel-tube junction.

In a preferred approach, channel capping is carried out in shellformation, core formation, or, more preferably, both. Followingcompletion of pellet manufacture, the completed pellet is released usingany effective method.

It should be noted that the invention is not limited with respect to theaforementioned methods of manufacture, and that other methods for makingthe pellet implants are possible, including modified versions of theaforementioned methods or entirely different methods known to those ofordinary skill in the art.

To scale up pellet manufacture, it will be appreciated that automationof one or more aspects of the method is desirable. For example, anautomated pin positioning means would be useful for moving the elongatedpin vertically into and through the pelleting tube and then withdrawingthe pin, wherein the pin would be withdrawn stepwise in a core-and-shellmanufacturing method such as that described above. As another example,an automated means for filling the funnel or a functionally equivalentreservoir with pelleting material, including shell material and corematerial, would be desirable, as would a reservoir cleaning techniqueand a pellet removal system. Other such automated means will be apparentto those of ordinary skill in the art and/or are described in thepertinent texts and literature.

It is to be understood that while the invention has been described inconjunction with a number of specific embodiments, the foregoingdescription as well as the examples that follow are intended toillustrate and not limit the scope of the invention. Other aspects,advantages and modifications will be apparent to those skilled in theart. All patents, patent applications, and publications mentioned hereare hereby incorporated by reference in their entireties.

EXPERIMENTAL

General Procedure A—Monolithic Pellet Manufacture:

Subdermally implantable monolithic pellets of the invention wereprepared in these examples using a hot melt method, as described below.

System preparation: A funnel as illustrated in the hot melt moldingsystem of FIGS. 2A and 2B was heated to a temperature just high enoughto render the pellet composition flowable. A length of PTFE tubing, cutto allow a seal to form between the heated funnel and the tubing, wasplaced into a heated collar to bring the temperature to just below thetransition temperature of the powder, i.e., the temperature at which thepowder transforms from a substantially solid form into a flowable form.The collar, with PTFE tube attached, was placed on a drawing pin suchthat the pin extended through the length of the tube, terminating justbelow the funnel. The pin is sized such that its diameter issufficiently close to the inner diameter of the PTFE tube to provide asealing fit therebetween. The funnel was then brought into contact withthe top of the heated collar and therefore with the pin as well, suchthat the channel's opening was aligned with the center of the pin,collar and tube. This arrangement created a seal between the channel'sopening and the upper region of the PTFE tubing.

Materials: cholesterol; phosphatidylcholine or lecithin; andetonogestrel.

Monolithic pellet preparation: All materials were fully dissolved inethanol, and the ethanol was then evaporated to leave a homogeneouscomposition of the pellet components as a powder. These materials may,alternatively, be slurried by hand or machine mixing in any USP gradeorganic solvent, with ethanol preferred. In formulations withfree-flowing dry powders, dry-mixing equipment, such as V-blenders orother type of blenders, may be used.

The powdery pellet composition was poured directly into the heatedfunnel. The amount of material added to the funnel was calculated toprovide enough material to fill the PTFE tubing cavity as well as createa residual in the funnel that capped off the PTFE tubing, therebycausing a complete fill of the cavity and preventing air from enteringand creating voids and cracks in the pellet. As the powdered materialreached its transition temperature and became flowable, the pin waslowered through the PTFE tubing, drawing the pellet composition into thetube and forming an elongated rod.

Pellet post processing: The rod was allowed to cool in ambientconditions in place for approximately 30 to 60 seconds prior to removingthe collar and PTFE tube for cooling at room temperature. Once the rodcooled, it was ejected from the PTFE tube with a pin and inspected. Itwas then available for trimming to predetermined pellet dimensions usinga hot knife.

General Procedure B—Manufacture of Core-and-Shell Pellets,Drug-Containing Core (“Core-Type Pellets”):

Modifications were made to the above procedure for making monolithicpellets in order to make core-and-shell pellets, i.e., subdermallyimplantable pellets with a drug-containing core in an inert shell. Thepellet manufacturing assembly used to make core-and-shell pellets isschematically illustrated in FIGS. 3A through 3E.

System preparation: The hot melt molding system was set up and readiedfor pellet manufacture as described above with respect to monolithicpellets.

Materials for the drug-containing core: cholesterol; phosphatidylcholineand/or lecithin; and etonogestrel.

Materials for the inert shell: lipid only, e.g., cholesterol and/orphosphatidylcholine.

Preparation: All core materials were fully dissolved in ethanol, and theethanol was then evaporated to leave a homogeneous composition of thecore components as a powder. Shell materials were slurried in ethanol,and the ethanol was then evaporated to leave a homogeneous compositionof the shell components as a powder.

In this case, in contrast to monolith manufacture, as described inGeneral Procedure A, a double pin was used to fabricate thecore-and-shell pellet in two stages. The double pin was made byassembling a narrower pin on top of and in axial alignment with thesomewhat wider pin used for monolith preparation, the narrower pinforming an extended narrower segment of an integral pin structure.

The powdery shell composition was poured directly into the heatedfunnel. The amount of material added to the funnel was calculated toprovide enough material to fill the PTFE tubing cavity, with thenarrower pin segment container therein, and create a residual in thefunnel that capped off the PTFE tubing. This resulted in completefilling the cavity and preventing air from entering and creating voidsand cracks in the shell. As the powdered material in the heated funnelbegan to coalesce and flow, the pin was lowered through the PTFE tubing,drawing the flowable shell material, along with the extended narrowersegment of the pin, into the tube and forming an elongated cylinderaround the narrower pin segment. The cylinder thus formed was composedof the shell composition and serves as the shell of the final pellet. Toform the core, the funnel was wiped clean of shell material and themixed core powder was then added into the funnel. After heating the corecomposition until flowable, the pin was drawn down a second time, sothat the narrower upper segment was withdrawn almost completely from thesolidified shell. The tight contact between the shell and pin, andbetween the tube and funnel, resulted in a partial vacuum as the pin iswithdrawn from the shell, thereby siphoning flowable core material fromthe funnel into the shell. The core was allowed to cool and hardenwithin the shell. The tube was then removed from the apparatus and thecore-and-shell pellet allowed to further cool at room temperature beforebeing extracted from the tube.

General Procedure C—Manufacture of Core-and-Shell Pellets,Drug-Containing Shell (“Shell-Type Pellets”):

Core-and-shell pellets with a drug-containing shell and an inert core(i.e., “shell-type pellets) were manufactured using the process ofGeneral Procedure B, except that the drug-containing material was addedto the funnel first to form the shell, and the inert material addedsecond to form the core.

Unless otherwise indicated, all percentages herein are weight % (wt. %),all ratios are weight ratios, and all width and length measurements arein millimeters.

Example 1 Monolithic Pellets: Effect of Pellet Diameter on Release Rateand Duration

Rod-shaped, substantially cylindrical monolithic pellets, havingidentical compositions but differing in diameter, were made usingGeneral Procedure A.

Composition: 85 wt. % etonogestrel (“ENG”), 3 wt. % phosphatidylcholine(“PC”), and 12 wt. % cholesterol (“CH”).

The pellets made were both 4 mm in length, with one pellet having adiameter of 1.7 mm (a “monolithic thin” type of pellet) and the otherpellet having a diameter of 2.8 mm (a “monolithic thick” type ofpellet). Drug release rate in 95.0% denatured ethanol (i.e., anhydrousethanol denatured with 5 vol. % methanol and 5 vol. % isopropanol) and5% deionized water was evaluated over a time period of about 30 minutes,as follows:

50.0 ml of the 95.0% ethanol dissolution medium were added to a 125 mLErlenmeyer flask, which was then sealed with paraffin film. Twocapillary tubes were inserted through the film and into the dissolutionmedium, and were connected to a peristaltic pump that circulated thesolution at 4 mL/min through a 0.2 mm path length quartz cuvette in aUV-Vis spectrometer. The pellet was dropped into the dissolution medium,which was stirred at room temperature in the flask on an orbital shakerset to 150 rpm. The absorbance was measured at 240 nm, as ENG absorbsstrongly at that wavelength while the excipients, CH and PC, do not.Absorbance measurements were taken at 1-second intervals for 15 to 180minutes until the spectrometer response remained constant, indicatingcomplete dissolution of the pellet.

The dissolution profiles are shown in FIG. 4. The thinner monolithicpellets clearly stopped ENG release much earlier than thicker, moretraditional pellets, and they also started with a lower dose. As may beseen in the figure, increasing the pellet diameter increased bothduration of drug release, i.e., the time period during which ameasurable drug concentration was seen, and the drug release rate.

Example 2 Monolithic Pellets: Effect of Pellet Length on Release Rateand Release Duration

Two groups of rod-shaped, substantially cylindrical monolithic pellets,having identical compositions but differing in length, were made usingGeneral Procedure A.

Composition: 85 wt. % ENG, 3 wt. % PC, and 12 wt. % CH.

The pellets made were both 2.8 mm in diameter, with one pellet having alength of 4 mm and another pellet having a length of 6 mm. Thedissolution profiles obtained using the methodology described in Example1 are shown in FIG. 5. As may be seen in the figure, the two pelletsreleased drug over a time period of similar duration, but the shorterpellets gave rise to a shallower slope for the decreasing rate ofetonogestrel release, meaning that the release rate for the longerpellets decreased faster than that of the shorter pellets.

Example 3 Core-Type Pellets: Release Rate and Duration

General Procedure B was followed to prepare pellets having a core of 85wt. % ENG, 12 wt. % CH, and 3 wt. % PC, and a shell of 97 wt. % CH and 3wt. % PC. The diameter of each core was 1.6 mm and each shell was 0.6 mmthick, giving a total pellet diameter of 2.8 mm. Pellet length was 4 mm.Drug release over time was evaluated in 95% ethanol as described inExample 1. Results are shown in the dissolution profile of FIG. 6 (seethe curve corresponding to the pellet length of 4 mm).

Example 4 Core-Type Pellets: Effect of Pellet Length on Release Rate andDuration

General Procedure B was followed to prepare core-type pellets having acore of 85 wt. % ENG, 12 wt. % CH, and 3 wt. % PC, and a shell of CH andPC in a 97:3 weight ratio. For purposes of evaluating the effect ofpellet length on release rate and duration with core-type pellets, acore pellet was prepared as in Example 3, but with a pellet length of 2mm. Drug release rate was evaluated as described in Example 1, and thedissolution profiles are shown in FIG. 6. Comparing the figure with therelease profiles of the monolithic pellets shows that the ENG releaserate is significantly slower with core-type pellets than with monolithicpellets. Doubling the core pellet length from 2 mm to 4 mm doubled theENG release duration while maintaining a fairly even ENG release rate ofapproximately 5 mg/hr.

Example 5 Shell-Type Pellets: Effect of Pellet Length on Release Rateand Duration

General Procedure C was followed to prepare shell-type pellets having acore of CH and PC in a 97:3 weight ratio and a shell of 85 wt. % ENG, 12wt. % CH, and 3 wt. % PC. The diameter of each core was 1.6 mm and eachshell was 0.6 mm thick. As in the preceding example, a first pellet wasprepared that was 2 mm in length, and a second pellet was prepared thatwas 4 mm in length. Drug release rate in ethanol was evaluated asdescribed in Example 1. The dissolution profiles for the two pelletgroups are shown in FIG. 7. In this case, increasing the length of thepellet did not substantially change the duration of ENG release, but didincrease ENG release rate. Shell pellets are designed to have a rapidcessation of ENG release once the shell has eroded to the CH core. Thiscan be seen with the 4 mm shell pellet, compared to the 4 mm monolithicpellet, but was not clearly seen in the 2 mm shell pellet.

For purposes of comparison, the dissolution profiles obtained for thethick monolithic pellets and thin monolithic pellets (Example 1) areshown as a group in FIG. 8A, with the dissolution profiles obtained forcore-type pellets (Example 3) and shell-type pellets (Example 5), allpellets 4 mm in length, shown in FIGS. 8B and 8C, respectively.

Example 6 Effect of Drug Concentration on Drug Release Profile

In order to assess the concentration of drug in the implant on the drugrelease profile, four types of pellets were made, with two drugconcentration subgroups prepared for each of the four pellet types:

Type (I), Monolithic thick pellets. Dimensions: Diameter, 2.8 mm,length, 6 mm. Type (I), subgroup (A): 85% ENG, 12% CH, 3% PC. Type (I),subgroup (B): 20% ENG, 77% CH, 3% PC.

Type (II), Monolithic thin pellets. Dimensions: Diameter, 1.7 mm;length, 4 mm.—Type (II), subgroup (A): 85% ENG, 12% CH, 3% PC. Type(II), subgroup (B): 20% ENG, 77% CH, 3% PC.

Type (III), Core-type pellets. Dimensions: Core diameter, 1.6 mm; shellthickness, 0.6 mm; length, 4 mm. Type (III), subgroup (A): 85% ENG, 12%CH, 3% PC core and 97% CH, 3% PC shell. Type (III), subgroup (B): 20%ENG, 77% CH, 3% PC core and 97% CH, 3% PC shell.

Type (IV), Shell-type pellets. Dimensions: Core diameter, 1.6 mm; shellthickness, 0.6 mm; length, 4 mm. Type (IV), subgroup (A): 85% ENG, 12%CH, 3% PC shell and 97% CH, 3% PC core. Type (IV), subgroup (B): 20%ENG, 77% CH, 3% PC shell and 97% CH, 3% PC core.

The release rate results obtained using the method of Example 1 can beseen in the comparative release profiles of FIGS. 9 through 12. With allfour pellet types, thick, thin, core and shell, the rate of ENG releaseincreased with an increase in ENG content, while the release durationdecreased with an increase in ENG content. While the approximatelyfour-fold greater ENG content in the 85% ENG pellets relative to the 20%ENG pellets might have been expected to give an approximately four-foldgreater release rate of ENG, the EN release from the 85% pellets was,surprisingly, substantially higher than four-fold faster. ENG releasefrom pellets with higher CH content is slowed because the aqueoussolubility of a 20% ENG/80% CH solid mixture is lower than onecontaining 85% ENG/15% CH.

Example 7 Effect of Changing Excipient on Drug Release Profile

In order to assess the impact of a change in excipient on drug releaseprofile from pellet implants, several monolithic pellets were made withdifferent excipient compositions but were otherwise identical. Pelletdimensions: diameter 2.8 mm, length 6 mm. Composition: 85% ENG, 15%excipient. Pellets were made with the excipients indicated below:

Excipient 1: CH/PC at a 4:1 weight ratio.

Excipient 2: Propylene glycol (PG).

Excipient 3: Polyethylene glycol 8000 (PEG-8000).

Excipient 4: Polyethylene glycol 300 (PEG-300).

Excipient 5: Palmitic acid (PA).

Dissolution profiles obtained using the method of Example 1 are providedin FIGS. 13 through 17 for Excipients 1 through 5, respectively.

At 85% ENG, this major component, i.e., the active agent, controlled theoverall release profile when relatively small molecules were used as theexcipient. The addition of a large polymeric molecule, PEG-8000, wasfound to inhibit ENG release and increase the release duration.

Example 8 In Vivo Evaluation

Five types of pellets were prepared using the procedures of the earlierexamples:

ENG thick monolithic (85% ENG, 12% CH, and 3% PC; diameter 2.8 mm,length 6 mm;

ENG thin monolithic (85% ENG, 12% CH, and 3% PC; diameter 1.7 mm, length4 mm;

ENG shell (core of CH/PG at a 97:3 ratio; shell of 85% ENG, 12% CH, and3% PG; core diameter 1.6 mm, shell thickness 0.6 mm, and length 4 mm;

ENG core (core of 85% ENG, 12% CH, and 3% PG; shell of CH/PC at a 97:3weight ratio; core diameter 1.6 mm, shell thickness 0.6 mm, and length 4mm; and

NET (norethindrone) thick monolithic (85% NET, 15% CH); diameter 2.8 mm,length 6 mm.

The five pellet types were implanted subcutaneously into eight rats perpellet type (except for NET thick monolithic, where pellet one waspulled out by the animal sometime during day 1). The number of pelletsimplanted per rat was chosen to keep the total ENG doses similar (32±5mg). Pellets were implanted separately on the animal's back. Ratsreceived a 1×ENG or NET thick monolithic pellet above one front leg, or2× shell pellets above both front legs, or 4× thin monolithic pellets orcore pellets above all four legs. Blood plasma levels were evaluated atday 1, day 4, day 14, day 30, and day 90. Extended release was achievedwith all pellets, as indicated by FIG. 18.

Then, the unreleased progestin per rat was averaged for each pellettype, and the amount released was calculated by difference from theaverage starting content based on the analysis of pellets made in thesame batches as those implanted. FIG. 19 shows that the amount ofprogestin initially released from the pellets tightly correlates withthe exposed surface area, supporting the same surface erosion mechanismin vivo as that seen in vitro, and also supporting a correlation betweenENG loss and blood levels, implying that the amount of drug released andthe rate of drug release can be controlled by varying exposed ENGsurface area. A good correlation showing a linear dose response wasfound between the blood concentration integrated over the three-monthexposure (i.e., the area under the curve or “AUC”) and the amount ofprogestin released from the pellets, as seen in FIG. 20.

We claim:
 1. A drug delivery system for use in female contraception,comprising: a subdermally implantable pellet that provides forcontrolled release of a contraceptive agent throughout an extended drugdelivery time period, the pellet comprising an amount of thecontraceptive agent that, following subdermal implantation of at leastone pellet into a female individual, results in a serum level of thecontraceptive agent sufficient to achieve contraceptive efficacy duringthe extended drug delivery time period, wherein the pellet (a) isbioerodible in situ; (b) has an elongated form with a first regioncomprising an inner core having a length, a surface along the length, afirst end, and an opposing second end, and a second region comprising anouter shell enclosing the surface of the inner core along its length butnot the first end or the second end, such that the inner core hasexposed surface area at the first and second ends, and further wherein(c) (i) at least about 80 wt. % of the contraceptive agent is present inthe core, (ii) at least about 80 wt. % of the contraceptive agent ispresent in the shell, or (iii) the core and the shell each contain atleast about 20 wt. % of the contraceptive agent.
 2. The drug deliverysystem of claim 1, comprising two to six pellets.
 3. The drug deliverysystem of claim 1, wherein the pellet is lipophilic.
 4. The drugdelivery system of claim 3, wherein any hydrophilic components in thepellet represent less than about 35 wt. % of the pellet.
 5. The drugdelivery system of claim 3, wherein the pellet comprises a solid attemperatures in the range of about 35° C. to about 40° C.
 6. The drugdelivery system of claim 1, wherein any inactive components containedwithin the pellet are bioresorbable and/or water soluble, or aretransformed in situ during pellet bioerosion into at least onebioresorbable and/or water-soluble species.
 7. The drug delivery systemof claim 1, wherein at least about 80 wt. % of the contraceptive agentis present in the core.
 8. The drug delivery system of claim 1, whereinat least about 80 wt. % of the contraceptive agent is present in theshell.
 9. The drug delivery system of claim 1, wherein the core and theshell each contain at least about 20 wt. % of the contraceptive agent.10. The drug delivery system of claim 1, wherein the core contains afirst contraceptive agent and the shell contains a second contraceptiveagent.
 11. The drug delivery system of claim 1, wherein the extendeddrug delivery time period comprises: (a) an effective drug delivery timeperiod during which the contraceptive agent is released at a dosagesufficient to provide contraceptive efficacy, and thereafter (b) asub-effective drug delivery tail period, during which the pelletcontinues to release the contraceptive agent but at a dosage below thatnecessary to provide contraceptive efficacy, wherein (a) is in the rangeof about six months to about four years.
 12. The drug delivery system ofclaim 11, wherein the tail period is at most about 12 months.
 13. Thedrug delivery system of claim 12, wherein the contraceptive agent isreleased at a rate that is substantially constant throughout theeffective drug delivery time period.
 14. The drug delivery system ofclaim 1, wherein the contraceptive agent comprises a progestogen. 15.The drug delivery system of claim 14, wherein the progestogen isselected from 21-acetoxypregnenolone, allylestrenol, anagestone,chlormadinone, chloroethynyl norgestrel, cyproterone, desogestrel,dienogest, dimethisterone, drospirenone, ethisterone, ethynerone,etynodiol, etonogestrel, gestodene, hydroxyprogesterone, levonorgestrel,lynestrenol, medrogestone, medroxyprogesterone, megestrol, nomegestrol,norethindrone, norelgestromin, noretynodrel, norgestimate, norgestrel,norgestrienone, progesterone, retroprogesterone, and combinations of anyof the foregoing.
 16. The drug delivery system of claim 15, wherein theprogestogen is etonogestrel.
 17. The drug delivery system of claim 15,wherein the progestogen is levonorgestrel.
 18. The drug delivery systemof claim 14, wherein the contraceptive agent further comprises anestrogenic compound.
 19. The drug delivery system of claim 1, whereinthe pellet has a pharmacokinetic profile determined by at least onepellet property selected from width, length, diameter, surface area,size, composition, hardness, and degree of crystallinity.
 20. The drugdelivery system of claim 1, wherein the pellet comprises a compositionthat is flowable at a selected temperature in the range of about 50° C.to about 250° C.
 21. A method for administering a contraceptive agent toa female individual in a sustained release manner over an extended drugdelivery time period, comprising subdermally implanting the drugdelivery system of claim 1 into the individual and allowing the drugdelivery system to remain in place throughout the extended drug deliverytime period.
 22. The drug delivery system of claim 7, wherein 100% ofthe contraceptive agent is present in the core.
 23. The drug deliverysystem of claim 8, wherein 100% of the contraceptive agent is present inthe shell.